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Mol Biol Evol. 2016 Dec;33(12):3161-3169. Epub 2016 Sep 15.

Cis-Regulatory Evolution of Forkhead Box O1 (FOXO1), a Terminal Selector Gene for Decidual Stromal Cell Identity.

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Systems Biology Institute, Yale University, West Haven, CT.
Systems Biology Institute, Yale University, West Haven, CT
Department of Ecology and Evolutionary Biology, Yale University, West Haven, CT.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Medical School, West Haven, CT.
Department of Obstetrics and Gynecology, Wayne State University.


Studies in human and mouse have shown that decidual stromal cells (DSC), which develop in the innermost lining of uterus, mediate placentation by regulating maternal immune response against the fetus and the extent of fetal invasion. Investigating when and how DSC evolved is thus a key step to reconstructing the evolutionary history of mammalian pregnancy. We present molecular evidence placing the origin of DSC in the stem lineage of eutherians (extant placental mammals). The transcription factor forkhead box O1 (FOXO1) is a part of the core regulatory transcription factor complex (CoRC) that establishes the cell type identity of DSC. Decidualization, the process through which DSC differentiate from endometrial stromal fibroblasts, requires transcriptional upregulation of FOXO1 Contrary to other examples in mammals where gene recruitment is caused by the origin of an alternative promoter, FOXO1 is transcribed from the same promoter in DSC as in endometrial stromal fibroblasts. Comparing the activities of FOXO1 promoters from human, mouse, manatee (Afrotheria), and opossum (marsupial) revealed that FOXO1 promoter evolved responsiveness to decidualization signals in the stem lineage of eutherians. This eutherian vs. marsupial pattern of promoter activity was not observed in some other cell types expressing FOXO1, suggesting that this cis-regulatory evolution occurred specifically in the context of the origin of DSC. Sequence comparison revealed eutherian-specifically conserved nucleotides that contribute to the eutherian promoter activity. We conclude that the cis-regulatory activity of a terminal selector gene for decidual stromal cell identity evolved in the stem lineage of eutherians supporting a model where decidual cells are a eutherian innovation.


Foxo1; cis-regulatory evolution; decidual cells.; mammalian pregnancy

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